ABSTRACT: Major depressive disorder (depression) affects over 16 million adults in the U.S. per year and is the second leading cause of disability. Current medications were discovered largely by serendipity and act non-specifically, leading to unwanted side effects in addition to suboptimal effectiveness. We believe that a better understanding of the underlying pathologies, such as deficits in reward processing due to stress, will lead to more specific, effective treatments. The objective of this grant is to determine how stress affects activity in the lateral habenula ? a brain region that encodes reward, is sensitive to stress, and is implicated in depression ? and how altered lateral habenula activity leads to diminished reward responsivity in mice. Although studies have found that stress induces plasticity in the lateral habenula, how stress affects in vivo activity and reward encoding in the lateral habenula is poorly understood. The dominant model in the field is that stress causes tonic hyperactivity in the lateral habenula, which contributes to depression. However, we recently discovered that acute stress severely alters phasic reward signaling in the lateral habenula, changing decreases in activity (normal reward response) into increases in activity (punishment-like response). Our hypothesis is that stress not only increases tonic activity in the lateral habenula, but also alters phasic signaling of reward, which decreases reward responsivity. We will test this hypothesis in mice using chronic, deep-brain imaging and electrophysiological recording of lateral habenula activity during reward consumption, before and after stress. Our hypothesis predicts that both acute and chronic stress alter phasic signaling of reward in the lateral habenula as animals become less responsive to reward behaviorally. We will test for causal effects of phasic lateral habenula reward signals on reward responsivity in mice by perturbing lateral habenula activity during reward consumption. Our hypothesis predicts that phasic inhibition of lateral habenula activity during reward consumption will reverse the deleterious effects of stress on reward responsivity. Conversely, we predict that increasing phasic lateral habenula activity during reward consumption will mimic the effects of stress on reward responsivity. We will also determine if stress increases tonic activity in the lateral habenula and whether changes in tonic activity contribute to aspects of reduced reward responsivity. This study is significant because it specifies a mechanism by which stress affects reward processing and localizes it to a region of the brain that is implicated in depression. Validation of our hypothesis will focus future efforts on characterization of the molecular mechanisms of these activity and reward signaling transformations, their role in altered decision-making, and identification of the inputs/outputs of the lateral habenula that are involved, potentially leading to new therapies that improve reward responsivity in depression.